Second-Generation Antiandrogens Confer Cognitive Toxicities in Prostate Cancer

“To our knowledge, these results are the first to suggest an association between second-generation [antiandrogens] and cognitive and functional toxic effects based on data from prospective [randomized controlled trials],” according to the authors of a systematic review published in JAMA Oncology.

Second-generation antiandrogen agents, including abiraterone (Zytiga), apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi), may yield an increased risk of cognitive and functional toxicities when used to treat patients with prostate cancer, according to findings from a systematic review published in JAMA Oncology.

Across 4 studies with a combined enrollment of 5267 patients, cognitive toxicities of any grade affected 2% to 8% of patients in the antiandrogen groups and 2% to 3% of those in the control groups. Antiandrogen treatment correlated with a more-than twofold increase in the risk of these effects vs control treatment (Risk ratio [RR], 2.10; 95% CI, 1.30-3.38; P = .002), with no evidence of heterogeneity observed (I2 = 53%; 95% CI, 0%-84%; P = .10).

Additionally, across 12 studies with a combined enrollment of 13,524 patients, fatigue of any grade affected 5% to 45% of patients in the antiandrogen groups and 2% to 42% in the control groups. Investigators similarly noted an increased risk of fatigue associated with antiandrogen treatment (RR, 1.34; 95% CI, 1.16-1.54; P <.001), with evidence of heterogeneity (I2 = 83%; 95% CI, 71%-90%; P <.001). There was also an association between greater median age and greater risk of fatigue (coefficient, 0.75; 95% CI, 0.04-0.12; P <.001).

“To our knowledge, these results are the first to suggest an association between second-generation [antiandrogens] and cognitive and functional toxic effects based on data from prospective [randomized controlled trials],” the investigators wrote.

“Our findings have practical implications for patient care. There is strong evidence that poor cognitive function and mental health are linked to worse outcomes and increased mortality among patients with cancer. Cognitive dysfunction might also decrease adherence to cancer treatment. Because use of second-generation [antiandrogens] is becoming more prevalent in prostate cancer treatment, there is an increasing need to identify and treat individuals experiencing adverse cognitive effects.”

This systematic review and meta-analysis included a total of 12 randomized controlled trials and a total of 13,524 patients. All of the included studies were multinational and conducted between 2008 and 2021. Investigators examined patients with nonmetastatic disease in 3 of these trials and assessed those with metastatic disease in the remainder.

Median ages across trials ranged from 67 to 74 years. Morever, median follow-up times ranged from 3.9 to 48.0 months. In addition to second-generation antiandrogens, patients in the intervention arms often received androgen deprivation therapy, docetaxel, or prednisone. Patients in the control arms received one of those therapies in combination with placebo.

Antiandrogen treatment also resulted in an 87% increased relative risk of falls of any grade vs the control regimens (RR, 1.87; 95% CI, 1.27-2.75; P = .001). There was also a statistically significant increase in falls of grade 3 or higher (RR, 1.72; 95% CI, 1.01-2.94; P = .05).

“This systematic review and meta-analysis of [randomized controlled trials] suggests that second-generation [antiandrogens] carry a statistically significantly increased risk of cognitive toxic effects, fatigue, and falls,” the investigators concluded. “Our work supports the need for further research to determine how to identify, prevent, and treat cognitive and functional toxic effects in patients treated with second-generation [antiandrogens].”

Investigators noted several potential limitations to these data, including an inability to account for time to event, the unavailability of data on baseline cognitive function, and study heterogeneity. Moreover, not all studies used the same toxicity classification.

Reference

Nowakowska MK, Ortega RM, Wehner MR, Nead KT. Association of second-generation antiandrogens with cognitive and functional toxic effects in randomized clinical trials: a systematic review and meta-analysis. JAMA Oncol. Published online May 25, 2023. doi:10.1001/jamaoncol.2023.0998